Long lasting ghrelin derivatives for the treatment of cancer cachexia

用于治疗癌症恶病质的长效生长素释放肽衍生物

• 批准号: 8523562
• 负责人: Tarik Soliman
• 金额: $ 28.83万
• 依托单位: EXTEND BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8523562
• 关键词: Acylation; Address; Affect; Affinity; Animal Cancer Model; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Biological Assay; Biological Availability; Body Weight; Body Weight decreased; Cachexia; Cancer Model; Cancer Patient; Cell Line; Cells; Cessation of life; Chronic Disease; Chronic Obstructive Airway Disease; Clinic; Complex; Congestive Heart Failure; Conjugated Carrier; Consumption; Coupled; Data; Desire for food; Development; Dose; Eating; Effectiveness; FDA approved; Fatigue; Frequencies; Funding; Growth; Growth Hormone Receptor; Half-Life; Health Care Costs; Hormones; Hospitalization; Human; Hyperphagia; In Vitro; Infection; Intravenous; Intravenous infusion procedures; Laboratories; Lead; Life Expectancy; Malignant Neoplasms; Methods; Modeling; Modification; Muscle; Patients; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Phase; Pituitary Gland; Preparation; Production; Property; Proteins; Quality of life; Rattus; Reporting; Research; Risk; Rivers; Route; Self-Administered; Side; Small Business Innovation Research Grant; Somatotropin; Subcutaneous Injections; Symptoms; Syndrome; Technology; Testing; Therapeutic; Therapeutic Effect; Therapeutic Uses; Time; Toxicology; Wasting Syndrome; Weight Gain; Work; acyl group; analog; base; cancer therapy; chemotherapy; deacylation; efficacy testing; ghrelin; improved; in vivo; increased appetite; muscle form; outcome forecast; public health relevance; receptor binding; response; skeletal muscle wasting; subcutaneous; therapeutic protein

DESCRIPTION (provided by applicant): Cachexia is a complex syndrome characterized by involuntary weight loss and skeletal muscle wasting that leads to fatigue, weakness and a loss of appetite that is not reversed by increased caloric consumption. More than half of all cancer patients develop cachexia and it is responsible for more than 40% of all cancer deaths. Numerous complications associated with cachexia include an impaired response to drug treatment, an increased chance of infection, a poor prognosis and a decreased quality of life. Currently, there are no FDA- approved treatments for cachexia, but the hormone ghrelin has recently emerged as a molecule with great potential. Several studies in both animals and humans have shown that ghrelin increases food intake resulting in increased body weight. Ghrelin also stimulates the release of growth hormone, resulting in increased muscle mass, and ghrelin is reported to have anti-inflammatory activity. However, the use of ghrelin as a treatment is limited for several reasons: 1) ghrelin must be dosed 2-3 times daily to see efficacy due to its inherently short half-life of 11 min; 2) deacylation of ghrelin to an inactive form occurs in less than 5 min; and 3) ghrelin is currently dosed intravenously to see a therapeutic effect. The studies proposed in this application address each of these issues, resulting in the development of a long-acting ghrelin derivative that could be dosed less frequently. Extend Biosciences has a proprietary carrier molecule that lengthens circulating half-life, but is small enough so as not to interfere with the activity of a peptide to which it is conjugated. We have previously shown that when our carrier is conjugated to ghrelin, we can extend the half-life 22-fold, which is a significant improvement over native ghrelin. Additionally, we have shown that in vitro, carrier-conjugated ghrelin has the same receptor binding affinity as unconjugated ghrelin. We have also demonstrated that the carrier molecule greatly improves the bioavailability of a small protein when administered subcutaneously. The studies proposed in this Phase I application will investigate the ability of our long-acting ghrelin to stimulate growth hormone release from pituitary cells and increase food intake and body weight in healthy rats. This will allow us to show the in vivo functionality of conjugated ghrelin. We will address the importance of acylation by testing a constitutively active form of conjugated ghrelin. We will then test the leading candidate from these studies in an established model of cancer-induced cachexia in rats. An additional exploratory aim is to test subcutaneous dosing of our long-acting ghrelin along with the traditional intravenous dosing. SBIR Phase II funding will focus on GLP production and additional in vivo and toxicology studies needed to begin human trials. Once fully developed, our long-acting ghrelin derivative would provide a patient-friendly cachexia therapy that would significantly improve the prognosis and quality of life in patients with cancer and also in patient with other chronic disorders such as congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD). This technology can improve half-life and bioavailability of other peptide therapeutics as well.

描述（由申请人提供）：恶病质是一种复杂的综合征，其特征是不自觉的体重减轻和骨骼肌萎缩，导致疲劳、虚弱和食欲不振，并且不能通过增加热量消耗来逆转。超过一半的癌症患者患有恶病质，占所有癌症死亡人数的 40% 以上。与恶病质相关的许多并发症包括对药物治疗的反应受损、感染机会增加、预后不良和生活质量下降。目前，尚无 FDA 批准的恶病质治疗方法，但饥饿素激素最近作为一种具有巨大潜力的分子出现。几项针对动物和人类的研究表明，生长素释放肽会增加食物摄入量，从而导致体重增加。生长素释放肽还刺激生长激素的释放，导致肌肉质量增加，据报道生长素释放肽具有抗炎活性。然而，由于以下几个原因，使用生长素释放肽作为治疗方法受到限制：1) 生长素释放肽必须每天服用 2-3 次才能看到疗效，因为它的作用 固有的半衰期较短，为 11 分钟； 2) 生长素释放肽在 5 分钟内脱酰为无活性形式； 3) 目前，胃饥饿素通过静脉注射来观察治疗效果。本申请中提出的研究解决了这些问题中的每一个，从而开发出一种可以减少给药频率的长效生长素释放肽衍生物。 Extend Biosciences 拥有一种专有的载体分子，可以延长循环半衰期，但足够小，以免 干扰与其缀合的肽的活性。我们之前已经证明，当我们的载体与 ghrelin 结合时，我们可以将半衰期延长 22 倍，这比天然 ghrelin 有了显着的改进。此外，我们还表明，在体外，载体缀合的生长素释放肽具有与未缀合的生长素释放肽相同的受体结合亲和力。我们还证明，当皮下施用时，载体分子极大地提高了小蛋白质的生物利用度。该一期申请中提出的研究将调查我们的长效生长素释放肽刺激垂体细胞释放生长激素并增加健康大鼠食物摄入量和体重的能力。这将使我们能够展示缀合的生长素释放肽的体内功能。我们将通过测试缀合生长素释放肽的组成型活性形式来解决酰化的重要性。然后，我们将在已建立的大鼠癌症诱发恶病质模型中测试这些研究中的主要候选药物。另一个探索性目标是测试我们的长效生长素释放肽的皮下给药以及传统的静脉给药。 SBIR 第二阶段资金将重点用于 GLP 生产以及开始人体试验所需的其他体内和毒理学研究。一旦完全开发出来，我们的长效生长素释放肽衍生物将提供一种对患者友好的恶病质疗法，显着改善癌症患者以及充血性心力衰竭（CHF）和慢性阻塞性肺病（COPD）等其他慢性疾病患者的预后和生活质量。该技术还可以提高其他肽疗法的半衰期和生物利用度。